World Health Organization defines asthma as one of the major non-communicable diseases, and it is also a major hazard to human life and survival. In China, because of the frequent occurrence of large-scale smog, the number of asthma patients is increasing. Therefore, the development of new anti-asthma drugs has far-reaching social benefits. Asthma is clinically classified into episodes (acute episodes and chronic episodes) and remissions based on the symptoms and pathological features of asthma. The episodes and remissions alternate. Airway hyperresponsiveness and inflammation still exist during the remissions (Swedin L, Saarne T, Rehnberg M, et al. Patient stratification and the unmet need in asthma. Pharmacol Ther, 2017, 169: 13-34.). With the deepening understanding of the disease mechanism, the focus of asthma treatment has shifted from the simple relief of acute airway smooth muscle spasm to the comprehensive treatment of prevention and treatment of airway inflammation. Modern biomedical research indicates that asthma is inflammation caused by a variety of inflammatory cells and cytokines, especially chronic airway inflammation involving mast cells, eosinophils, T cells, and white blood cells. A variety of inflammatory factors including leukotrienes (LTC), interleukin (IL), and histamine are also involved.
Recent studies have found that the release of leukotrienes is one of the ultimate common pathways in a variety of different factors that cause inflammation and airway obstruction, having many different effects on the respiratory system. Leukotrienes are eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid and the essential fatty acid eicosapentaenoic acid by the enzyme arachidonate 5-lipoxygenase (5-LO). The name leukotriene comes from the words leukocyte and triene. Studies have shown that LTC4 has the strongest inflammatory activity among various leukotrienes (Schmidt D, Rabe K F., The role of leukotrienes in the regulation of tone and responsiveness in isolated human airways, Am J Respir Crit Care Med, 2000, 161 (2 Pt 2): 562-6.). Therefore, inhibition of LTC4 production and blocking of LTC4 binding to leukotriene receptors are important methods for the treatment of respiratory inflammation-related diseases including asthma and chronic obstructive pulmonary disease.
According to the Guidance of the Global Asthma Prevention and Control Initiative, inhibition of the leukotriene pathway can improve lung function and significantly improve bronchial asthma symptoms. Therefore, leukotriene modulators have been classified as drugs for controlling asthma symptoms and reducing seizures. The clinical efficacy of this class of drugs has been widely confirmed (Arakawa H, Hamasaki Y, Kohno Y, et al. Japanese guidelines for childhood asthma 2017. Allergol Int, 2017, 66(2): 190-204). Currently, there is only one anti-asthma drug based on inhibition of leukotriene production: ZILEUTON, a 5-lipoxygenase (5-LO) inhibitor. The development of novel leukotriene production inhibitors has broad application prospects and commercial value.
When studying the pharmacological activity of spiro aryl isoxazoline compounds, inventors found that the alantolactone/isoalantolactone spiro aryl isoxazoline compounds (as shown in Formulae I and II) can significantly inhibit the production of LTC4 in the mast cell. Further studies found that the half-inhibitory concentration of representative compounds reaches 71.21 nM, which is the highest activity to inhibit LTC4 production reported in the literature. Such compounds are lead compounds and drug candidates for anti-inflammatory and anti-asthmatic drug discovery based on the regulation of the leukotriene pathway.